Method for the synthesis of a benzimidazole compound

ABSTRACT

A process for the manufacture of omeprazole or esomeprazole from pyrmethyl alcohol via pyrmethyl chloride and pyrmetazole characterized in that the whole reaction sequence is carried out without any isolation or purification of intermediates. Further, the reaction is carried out in a solvent system common for the whole reaction sequence and inert to the reactants formed during the process and used in the process and comprises a water immiscible organic solvent and a specified amount of water.

This application is a continuation of U.S. patent application Ser. No.10/531,412, filed 14 Apr. 2005, now U.S. Pat. No. 7,227,024, which is a§371 of PCT/SE2003/001602, filed 15 Oct. 2003.

The present invention relates to an improved process for the synthesisof5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio)-1H-benzimidazole(pyrmetazole) used in the manufacturing of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazoleand its (S)-enantiomer, known under the generic names omeprazole andesomeprazole, respectively.

BACKGROUND OF THE INVENTION AND PRIOR ART

An efficient process for synthesis of omeprazole is described in WO97/22603, which is hereby incorporated by reference. In the describedprocess, there is no need for additional purification or isolation stepsin between the different reaction steps and a more efficient process ishence offered. Further adding to the simplicity, the reaction sequenceis carried is out in one common solvent system throughout the wholeprocess. However, there is still a need of a new, even more convenientand more efficient process for the manufacturing of pyrmetazole inhigher yield and with higher purity, and which process providesincreased yield of the final products, omeprazole or esomeprazole.

SUMMARY OF THE INVENTION

The object of the invention is to provide a process for themanufacturing of pyrmetazole in a high yield and with a high purity,which is especially important for the asymmetric synthesis ofesomeprazole. The process, i.e. the reaction sequence from pyrmethylalcohol (Ia) to pyrmetazole (I), is carried out, without any isolationor purification of intermediates, in one solvent system common for thereaction sequence, to obtain a reproducible high yield of the finalproducts, omeprazole or esomeprazole. Such a process eliminates timeconsuming steps for isolation or purification of intermediates and savetime on avoiding solvent changes in the process, thus making the processmore efficient and with a high production capacity.

DETAILED DESCRIPTION OF THE INVENTION

The process comprising the following reaction steps:

Step 1: Pyrmethyl alcohol (Ia)+chloro-dehydroxylating agent→pyrmethylchloride (Ib)

Step 2: Pyrmethyl chloride (Ib)+metmercazole (Ic)→pyrmetazole (I) isperformed in a solvent system common for the reaction sequence,comprising a water immiscible organic solvent and a specified amount ofwater added. This process is used for the synthesis of pyrmetazole, anintermediate in the synthesis of omeprazole or esomeprazole.

In Step 1, the conversion of pyrmethyl alcohol into pyrmethyl chloride,hereinafter referred to as chloro-dehydroxylation, the pyrmethyl alcohol(Ia) is reacted with an excess of a chloro-dehydroxylating agent givingan alkyl chloride, i.e. pyrmethyl chloride (Ib). Thechloro-hydroxylating agent can be selected from thionyl chloride,cyanuric chloride, phosphorous trichloride, phosphorous pentachloride,and phosphorous oxychloride. The reaction is performed at a temperatureof −5° C. to +45° C., preferably between −5° C. and +35° C., mostpreferably between +10° C. and +35° C., or between +25° C. and +35° C.In the case, where no water is present from the beginning, theconversion of the reactants into the product, pyrmethyl chloride (Ib),will not go to completion. However, the reaction can be re-started byadding a specified amount of water and the reaction thereafter can becompleted. Thus, if the reaction ceases, it is possible to re-start itwith addition of a specified amount of water.

According to Step 2 above, pyrmethyl chloride (Ib), provided from Step1, is reacted with metmercazole (Ic) under alkaline conditions, e.g. analkaline aqueous solution of metmercazole (Ic) is prepared and mixedwith the pyrmethyl chloride (b). The reaction is preferably carried outat a temperature of +30° C. to +60° C. during a prolonged period oftime. Metmercazole (Ic) is charged in approximately stoichiometricamount to the pyrmethyl chloride (Ib). The invention may also be used incombination with a phase transfer catalyst, for instance a quarternaryamine, such as tetrabutyl ammonium bromide. The two phases formed areseparated, the aqueous phase may be extracted with a water imiiscibleorganic solvent such as toluene, and the organic phase may be extractedwith water.

As pyrmethyl alcohol (Ia) has a disadvantageous effect on the followingreaction steps, it is important to minimise the content of the pyrmethylalcohol (Ia) present.

The reaction sequence according to Step 1 and Step 2 described above iscarried out in one solvent system. The solvent system used for thepresent reaction sequence comprises a water immiscible organic solvent,such as halogenated, aliphatic or aromatic hydrocarbons or esters, forexample toluene, ethyl-acetate and methylene chloride, and a specifiedamount of water added. Preferably, toluene may be used as the waterimmiscible organic solvent.

The water content in the solvent system shall preferably be near orabove the saturation point of the organic solvent used. By this, ahigher amount of pyzmethyl alcohol (Ia) is allowed to react and form thepyrmethyl chloride (Ib). The amount of water may be added before, duringor after the charging of the chloro-dehydroxylating agent, such asthionyl chloride. An optimum range of water present during Step 1 isbetween 0.3 and 5.5 mg water/ml of water immiscible organic solvent,preferably between 0.3 and 5.0 mg water/ml, or between 0.4 and 2.4mg/ml, and most preferably between 1.0 and 2.4 mg/ml. If the watercontent is lower than the saturation point of the organic solvent usedi.e. for toluene, less than 0.3 mg/ml, the reaction is slow and it has atendency to stop before full conversion has been achieved. In average, aconversion of 25-50% is obtained when toluene, having a water content ofless than 0.1 mg/ml, is used as the solvent system. Such a reactionleads to a high content of pyrmethyl alcohol (Ia) in the reactionmixture after Step 1. It is inconvenient to have a high content ofpyrmethyl alcohol present in the crude product of pyrmetazole (I) afterStep 2. We have found that if about 1%, or more, of pyrmethyl alcohol(Ia) is left in the reaction mixture, this component has an adverseeffect on both the turnover and the enantioselectivity achieved in theasymmetric oxidation of pyrmetazole into esomeprazole.

The present invention is an improvement of the first two steps in theprocess described in WO 97/22603. The reaction sequence, from pyrmethylalcohol (Ia) via pyrmethyl chloride (Ib) to pyrmetazole (I), is carriedout in one common solvent system, comprising a water immiscible organicsolvent and a specified amount of water, which is used throughout thereaction sequence. The new improved process for the manufacture of5-methoxy-2(((4-mehoxy-3,5-dimethyl-2-pyridinyl)-methyl)-thio)-1H-benzimidazole(pyrmetazole) can in more detail be described by Step 1 and Step 2below, both performed in a water immiscible organic solvent and with aspecified amount of water added:

Step 1: Chloro-dehydroxylation:

Reacting (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl alcohol (pyrmethylalcohol) of the formula Ia

with a chloro-dehydroxylating agent, such as thionyl chloride, providing(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl chloride (pyrmethyl chloride)of the formula Ib

Step 2: Coupling Reaction:

Reacting (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl chloride of theformula Ib, prepared in Step 1 above, with2-mercapto-5-methoxybenzimidazole (metmercazole) of the formula Ic

in the presence of a base such as, sodium hydroxide or potassiumhydroxide; providing 5-methoxy-2(((4-methoxy3,5-dimethyl-2-pyridinyl)methyl)thio)-1H-benzimidazole (pyrmetazole) ofthe formula I

The pyrmetazole is then further processed to the final products,omeprazole or esomeprazole.

The present invention provides an improvement associated to Step 1 inthe manufacturing of pyrmetazole, by a more complete conversion andreproducible yield of pyrmethyl alcohol (Ia) and pyrmethyl chloride (Ib)respectively. The advantageous effect of water present during thechloro-dehydroxylation reaction, Step 1, is surprisingly as this type ofchloro-dehydroxylating agents are regarded as incompatible with water,i.e. thionyl chloride reacts violently with water and excess of thionylchloride is usually hydrolysed after a reaction by an addition of water.

More specifically, the aim with the present invention has been toimprove Step 1, the chloro-dehydroxylation step, in the process forpreparation of pyrmetazole (I) used in the synthesis of omeprazole oresomeprazole, i.e. to obtain a more efficient conversion of thepyrmethyl alcohol (Ia), a reaction step that is common for both thesynthesis of esomeprazole and omeprazole. It has, surprisingly, beenshown that presence of a specified amount of water reduces the amount ofremaining pyrmethyl alcohol (Ia) i.e. the conversion of pyrmethylalcohol (Ia) according to Step 1 is more complete. A small amount ofwater present in the reaction mixture lead to a better conversion, and amore efficient use of pyrmethyl alcohol (Ia) and a product of high yieldand high purity.

According to the process described in WO 97/22603 the crude product,pyrmetazole (I), from Step 2 is further processed to omeprazole in aconsequtive reaction sequence. There is no isolation or purificationperformed during the reaction sequence, which is preferable with respectto process simplicity and economy. However, residues of pyrmethylalcohol (Ia) from Step 1 have been found in the product mixture ofpyrmetazole (I) in Step 2.

It has been found that traces of pyrmethyl alcohol (Ia) havedisadvantageous effects upon the oxidation of pyrmetazole (I) toomeprazole and especially then in the asymmetric oxidation ofpyrmetazole (I) to esomeprazole. Such traces of pyrmethyl alcohol (Ia)results in reduced turnover and enantio-selectivity in the asymmetricoxidation and give a product with less purity and in lower yield. Thus,the obtained enantiomeric excess of esomeprazole is depending on a highpurity of the intermediate compound pyrmetazole (I). The impact oflevels from about 1% or above of pyrmethyl alcohol has beeninvestigated.

The presence of water in the chloro-dehydroxylation reaction, Step 1, isof outmost importance to obtain pyrmethyl chloride (Ib) and therebypyrmetazole (I) in high yield and with a high purity without anyrequirements of isolation or purification. The required amount of watermay be charged from the beginning, or being added during or after theaddition of a suitable chloro-dehydroxylating agent, such as thionylchloride. Preferably a small specified amount of water is charged at thebeginning of the reaction. The addition of water during the process mayalso be used as a way to re-start an incomplete reaction to improve theyield and product purity. The present invention provides a moreefficient use of the chloro-dehydroxylating agent.

Furthermore, the presence of water in Step 1 provides a safer, and morerobust process, as it also reduces the different risks connected withthis type of reactions, i.e. such as accumulation of thionyl chloride orreactive reaction intermediates. Thus, avoiding the risk of a late rapidexothermic reaction to occur. However, there exists other options to getcomplete and/or high conversion of pyrmethyl alcohol (Ia) in Step 1, andto avoid, or minimise, traces of pyrmethyl alcohol (Ia) in Step 2, Theseoptions can be, for instance, an extended reaction time, raised reactiontemperature or increased excess of thionyl chloride. However, theseoptions are not favored in view of an effective production of the finalproducts, omeprazole and esomeprazole.

The examples that follow will further illustrate the improved process ofthe invention. These examples are not intended to limit the scope of theinvention as defined hereinabove or as claimed below.

EXAMPLES Example 1

Pyrmethyl alcohol, 8.82 g (52.7 mmol), was dissolved in toluene,saturated with water, 74 ml (water content 0.4 mg/ml according to KarlFisher titration). To the stirred solution, at 10° C., thionyl chloride,8.15 g (68.5 mmol), was added slowly over 60 minutes (flow rate 0.083ml/min). A white precipitate was formed. The conversion of pyrmethylalcohol into pyrmethyl chloride was followed by HPLC, (column: Nova-PakC 18, 4 μm 3.9*150 mm). A fast reaction was recorded, reaching 99%conversion after completed addition of thionyl chloride.

Example 2

Pyrmethyl alcohol, 8.81 g (52.6 mmol), was dissolved in a mixture oftoluene, 75 ml (water content 0.04 mg/ml according to Karl Fishertitration) and water, 180 μl (10 mmol, equivalent to about 2.4 mg/ml ofwater in toluene). To the stirred solution, at 10° C., thionyl chloride,8.15 g (68.5 mmol), was added slowly over 60 minutes (flow rate 0.083ml/min). A white precipitate was formed. The conversion of pyrmethylalcohol into pyrmethyl chloride was followed by HPLC as in Example 1. Afast reaction was recorded, reaching 99% conversion after completedaddition of thionyl chloride. The reaction temperature was adjusted to20° C. and methanol, 40 ml, was added to stop the reaction. A solutionof the crude product, pyrmethyl chloride was obtained, with a purity of99.6% (HPLC), and with a pyrmethyl alcohol residue of 0.3%.

Example 3

Pyrmethyl alcohol, 8.82 g (52.7 mmol), was dissolved in toluene, 75 ml(water content 0.04 mg/ml according to Karl Fisher titration). To thestirred solution, at 10° C., thionyl chloride, 8.15 g (68.5 mmol), wasadded slowly over 60 minutes (flow rate 0.083 ml/min). A whiteprecipitate was formed immediately. The obtained reaction mixture wasstirred and the reaction followed by HPLC, as in Example 1, for anadditional 3.5 hours (conversion declined and stopped at about 30%).Water, 180 μl (10 mmol), was added, to re-start the reaction, yielding ahigh conversion (>90%) within 30 minutes after the addition.

Example 4

Pyrmethyl alcohol (8.8 g, 52.6 mmol) was dissolved in toluene (75 ml,water content 0.12 mg/ml) moistened with water (180 μl, 10 mmol) at roomtemperature. To the stirred solution, at 25-30° C., thionyl chloride(8.15 g, 68.5 mmole) was added slowly over 60 min. (flow rate of 0.083m/min). Conversion of the reaction was analysed with HPLC as inExample 1. Conversion over 99.5%. Water (2.3 ml) was added to quench anyexcess of thionyl chloride.

An alkaline (13.5 g, 168.3 mmol 50% w/w sodium hydroxide) aqueous (80ml) solution of metmercazole (9.8 g, 54.2 mmol) was added followed byadditional sodium hydroxide (8.8 g, 110.5 mmol, 50% w/w sodiumhydroxide) to reach pH>12.5. The temperature was allowed to increase to45° C. during the additions. The reaction mixture was left with vigorousstirring for approximately two hours at 45° C. The agitating wasinterrupted and the phases were left to separate. The aqueous phase wasdiscarded. The organic phase, comprising pyrmetazole, was washed withwater and was analysed for residues of pyrmethyl alcohol (less than 0.1%mol).

Example 5

Pyrmethyl alcohol (8.8 g, 52.6 mmol) was dissolved in toluene (75 ml,water content 0.12 mg/ml) moistened with water (375 μl, 20.8 mmol) atroom temperature. To the stirred solution, at 25-35° C., thionylchloride (9.33 g, 78.4 mmol) was added slowly over 60 min. (flow rate of0.095 ml/min). Conversion of the reaction was analysed with HPLC as inExample 1. Conversion over 99.5%.

The synthesis continued in the same way as described in Example 4. Theproduct phase, comprising pyrmetazole, was analysed for residue ofpyrmethyl alcohol (less than 0.1% mol).

1. A process for the manufacture of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-thio]-1H-benzimidazoleof formula I,

the process comprising the following reaction steps carried out in aconsecutive order in a solvent system without isolation of theintermediates formed during the process: a) reacting(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl alcohol (pyrmethyl alcohol)of formula Ia,

with a chloro-dehydroxylating agent to obtain(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl chloride (pyrmethyl chloride)of formula Ib; and

b) reacting the (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl chloride offormula Ib with 2-mercapto-5-methoxybenzimidazole (metmercazole) offormula Ic,

in the presence of a base to obtain5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole(pyrmetazole) of formula I; wherein the solvent system is the same forthe entire reaction sequence and comprises an organic solvent selectedfrom the group consisting of toluene, ethyl acetate and methyl chlorideand an amount of water in the range of between 0.3 and 5.5 mg water perml of the organic solvent.
 2. The process according to claim 1, whereinthe organic solvent is toluene.
 3. The process according to claim 1,wherein the organic solvent is ethyl acetate.
 4. The process accordingto claim 1, wherein the water is present at the start of step a).
 5. Theprocess according to claim 1, wherein the water is added during chargingof the chloro-dehydroxylating agent.
 6. The process according to claim1, wherein the water is added after charging of thechloro-dehydroxylating agent.
 7. The process according to claim 1,wherein the amount of water is between the saturation point of theorganic solvent and 5.5 mg/ml of the organic solvent toluene ormethylene chloride.
 8. The process according to claim 1, wherein theamount of water is in the range of 1.00-5.5 mg/ml of the organicsolvent.
 9. The process according to claim 1, wherein the amount ofwater is in the range of 1.0-2.4 mg/ml of the organic solvent.
 10. Theprocess according to claim 1, wherein the reaction in step a) is carriedout at a temperature in the range of between −5° C. and +45° C.
 11. Theprocess according to claim 1, wherein the reaction in step a) is carriedout at a temperature in the range of between −5° C. and +35° C.
 12. Theprocess according to claim 1, wherein the reaction in step a) is carriedout at a temperature in the range of between +10° C. and +35° C.
 13. Theprocess according to claim 1, wherein the reaction in step a) is carriedout at a temperature in the range of between +25° C. and +35° C.
 14. Theprocess according to claim 1, wherein the chloro-dehydroxylating agentis thionyl chloride.
 15. The process according to claim 1, furthercomprising adding an additional amount of water to the organic solventduring step a) after the start of the reaction.
 16. The processaccording to claim 1, wherein the reaction in step b) is carried out ata temperature in the range of between +30° C. and +60° C.
 17. Theprocess according to claim 7, wherein the organic solvent is toluene.